RESUMO
Tadalafil, a phosphodiesterase 5 inhibitor, is being investigated as a treatment for pulmonary arterial hypertension (PAH) in children aged 6 months to less than 18 years. Tadalafil pharmacokinetic (PK) data in children less than 2 years old are unavailable, therefore a physiologically based pharmacokinetic (PBPK) model was developed to enable estimation of tadalafil doses in children less than 2 years old. The model was verified in adults and extended for use in children by modifying CYP3A-mediated intrinsic clearance to include CYP3A7. To account for co-dosing of the commonly prescribed moderate CYP3A4 inducer bosentan, predicted exposures were increased by a factor of 1.54 based on changes in exposure in adults with PAH. This factor was predictable using a bosentan PBPK model. The tadalafil model was verified in children aged greater than or equal to 2 years by comparing predicted and observed exposures. Tadalafil doses for children less than 2 years old were calculated as target area under the concentration curve from zero to 24 h (AUC0-24 )/predicted AUC0-24 , with target AUC0-24 of 10,000 ng*h/ml based on adult 40 mg single dose exposures determined in patients without bosentan background treatment. These doses were 2 mg, 3 mg, 4 mg, and 6 mg, respectively, for children aged birth to less than 1 month, 1 month to less than 6 months, 6 months to less than 1 year, and 1 to less than 2 years. Due to uncertainties in CYP maturation, a nonmechanistic steady-state volume scalar, and lack of PK data in children less than 2 years old, accumulation of tadalafil to steady-state in children less than 2 years was not verifiable. Safety of proposed doses is supported by postmarketing research and investigator-led trials.
Assuntos
Hipertensão Arterial Pulmonar , Adulto , Bosentana , Criança , Pré-Escolar , Indutores do Citocromo P-450 CYP3A , Humanos , Lactente , Inibidores da Fosfodiesterase 5/farmacocinética , Inibidores da Fosfodiesterase 5/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Tadalafila/farmacocinéticaRESUMO
AIM: Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome is a rare condition with an estimated prevalence rate of 0.3 per 100,000 people. Patient perspectives on healthcare experiences and quality of life have not yet been studied in depth. This novel study aimed to explore one person's lived experience of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome, taking into consideration healthcare experiences in relation to diagnosis and treatment. METHOD: A mixed-method design was used; one participant completed a semi-structured interview and three self-report measures: Hospital Anxiety and Depression Scale; World Health Organisation Quality of Life Scale (brief); Brief Illness Perception Questionnaire. RESULTS: Three qualitative themes appeared to influence the participant's healthcare experiences and quality of life: (1) Diagnosis and treatment, (2) identity and adjustment, and (3) recovery. Diagnosis and treatment summarised the patient's journey to receiving her diagnosis and the difficulties with treatment for this condition. Identity and adjustment included pre and post-diagnosis identity, frustrations and coping strategies. Recovery included experiences of progression and decline and service provision. CONCLUSION: All Multidisciplinary Team (MDT) interventions for Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome should be person-centred and focus on identity and personal strengths. Further research and service development should be completed to increase awareness and understanding of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome, promote patient wellbeing, reduce psychological distress, and facilitate engagement in neurorehabilitation.Implications for rehabilitationPolyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome is a rare condition and incorrect diagnoses and treatment have a significant impact on patients' physical and psychological wellbeing.Patients and families require support through person-centred care and good communication and continuity of care between multiple services.Multi-disciplinary interventions which focus on identity and strengths were beneficial for the participant in this case study.Further research and education are needed to increase knowledge on patient experiences of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome and continue to improve service provision.
Assuntos
Síndrome POEMS , Paraproteinemias , Atenção à Saúde , Feminino , Humanos , Síndrome POEMS/diagnóstico , Síndrome POEMS/terapia , Qualidade de VidaRESUMO
Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.
Assuntos
Aminopiridinas/metabolismo , Aminopiridinas/farmacocinética , Benzimidazóis/metabolismo , Benzimidazóis/farmacocinética , Quinases Ciclina-Dependentes/metabolismo , Quinases Ciclina-Dependentes/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Administração Oral , Adulto , Idoso , Alcinos/farmacocinética , Aminopiridinas/administração & dosagem , Aminopiridinas/sangue , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/sangue , Benzoxazinas/farmacocinética , Bosentana/farmacocinética , Claritromicina/administração & dosagem , Claritromicina/farmacocinética , Simulação por Computador , Quinases Ciclina-Dependentes/administração & dosagem , Quinases Ciclina-Dependentes/sangue , Ciclopropanos/farmacocinética , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Diltiazem/farmacocinética , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Itraconazol/farmacocinética , Cetoconazol/farmacocinética , Masculino , Pessoa de Meia-Idade , Modafinila/farmacocinética , Modelos Biológicos , Rifampina/administração & dosagem , Rifampina/farmacocinética , Verapamil/farmacocinéticaRESUMO
We verified a physiologically-based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5-mediated drug-drug interactions (DDIs). A midazolam (MDZ)-ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics-informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (FG ) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400 mg KTZ, which was, respectively, 2.7-3.4 and 3.9-4.7-fold in intravenous administration and 11.4-13.4 and 17.0-19.7-fold in oral administration, with AUCR numerically lower (P > 0.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A-mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers.
Assuntos
Citocromo P-450 CYP3A/genética , Cetoconazol/administração & dosagem , Midazolam/farmacocinética , Modelos Biológicos , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas , Genótipo , Humanos , Intestino Delgado/metabolismo , Cetoconazol/farmacologia , Fígado/metabolismo , Espectrometria de MassasRESUMO
The drug-drug interaction profile of atorvastatin confirms that disposition is determined by cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptides (OATPs). Drugs that affect gastric emptying, including dulaglutide, also affect atorvastatin pharmacokinetics (PK). Atorvastatin is a carboxylic acid that exists in equilibrium with a lactone form in vivo. The purpose of this work was to assess gastric acid-mediated lactone equilibration of atorvastatin and incorporate this into a physiologically-based PK (PBPK) model to describe atorvastatin acid, lactone, and their major metabolites. In vitro acid-to-lactone conversion was assessed in simulated gastric fluid and included in the model. The PBPK model was verified with in vivo data including CYP3A4 and OATP inhibition studies. Altering the gastric acid-lactone equilibrium reproduced the change in atorvastatin PK observed with dulaglutide. The model emphasizes the need to include gastric acid-lactone conversion and all major atorvastatin-related species for the prediction of atorvastatin PK.
Assuntos
Atorvastatina/farmacocinética , Gastroparesia/complicações , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Lactonas/química , Proteínas Recombinantes de Fusão/farmacocinética , Atorvastatina/administração & dosagem , Células Cultivadas , Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Interações Medicamentosas , Ácido Gástrico/metabolismo , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacocinética , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Modelos Biológicos , Transportadores de Ânions Orgânicos , Proteínas Recombinantes de Fusão/administração & dosagemRESUMO
This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.
Assuntos
Simulação por Computador , Aprovação de Drogas , Modelos Biológicos , Farmacocinética , Europa (Continente) , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
LY2623091 is a selective, orally active, nonsteroidal, competitive mineralocorticoid receptor antagonist that blocks the actions of aldosterone and other mineralocorticoid receptor ligands at the receptor level. The aim of this work was to explore and establish a population pharmacokinetic model, quantify the degree of interindividual variability, and identify significant disease-, patient-, and study-specific covariates that alter the disposition of LY2623091. The data included concentrations from 294 healthy subjects and patients with hypertension and/or chronic kidney disease (CKD), sampled in 5 phase 1 and 2 studies. The pharmacokinetics of LY2623091 was well described by a 2-compartment model with first-order absorption and elimination. Formulation (on oral bioavailability) as well as weight and age (both on apparent central volume of distribution) were found to be significant covariates. The relative bioavailability of the capsule formulation was 68.4% compared to that of the solution. Hypertension and CKD status were not significant covariates. The pharmacokinetic model suggests that given the same dose, patients with hypertension and/or CKD would receive a similar exposure compared to subjects without these disease conditions.
Assuntos
Hipertensão/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Modelos Biológicos , Insuficiência Renal Crônica/metabolismo , Adolescente , Adulto , Idoso , Disponibilidade Biológica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/sangue , Insuficiência Renal Crônica/sangue , Adulto JovemRESUMO
The κ-opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently developed KOR antagonist with high affinity and selectivity and showed efficacy in the suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (0.5-25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography scans with the KOR antagonist radiotracer (11)C-LY2795050 were conducted at baseline, 2.5 hours postdose, and 24 hours postdose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy (rmax) and IC50. LY2456302 dose dependently blocked the binding of (11)C-LY2795050 and nearly saturated the receptors at 10 mg, 2.5 hours postdose. Thus, a dose of 10 mg of LY2456302 appears well suited for further clinical testing. Based on the pharmacokinetic (PK)-RO model, the rmax and IC50 of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that rmax is 100%, IC50 was estimated as 0.83 ng/ml.
Assuntos
Benzamidas/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono/metabolismo , Tomografia por Emissão de Pósitrons , Pirrolidinas/metabolismo , Receptores Opioides kappa/metabolismo , Adulto , Benzamidas/farmacologia , Encéfalo/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Pirrolidinas/farmacologia , Adulto JovemRESUMO
PURPOSE: To develop a population physiologically-based pharmacokinetic (PBPK) model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that allows extrapolation and prediction of their concentration profiles in liver (efficacy) and muscle (toxicity). METHODS: SV/SVA plasma concentrations (34 healthy volunteers) were simultaneously analysed with NONMEM 7.2. The implemented mechanistic model has a complex compartmental structure allowing inter-conversion between SV and SVA in different tissues. Prior information for model parameters was extracted from different sources to construct appropriate prior distributions that support parameter estimation. The model was employed to provide predictions regarding the effects of a range of clinically important conditions on the SV and SVA disposition. RESULTS: The developed model offered a very good description of the available plasma SV/SVA data. It was also able to describe previously observed effects of an OATP1B1 polymorphism (c.521 T > C) and a range of drug-drug interactions (CYP inhibition) on SV/SVA plasma concentrations. The predicted SV/SVA liver and muscle tissue concentrations were in agreement with the clinically observed efficacy and toxicity outcomes of the investigated conditions. CONCLUSIONS: A mechanistically sound SV/SVA population model with clinical applications (e.g., assessment of drug-drug interaction and myopathy risk) was developed, illustrating the advantages of an integrated population PBPK approach.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Modelos Biológicos , Sinvastatina/análogos & derivados , Ativação Metabólica , Disponibilidade Biológica , Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Farmacogenética , Polimorfismo Genético , Reprodutibilidade dos Testes , Sinvastatina/administração & dosagem , Sinvastatina/efeitos adversos , Sinvastatina/sangue , Sinvastatina/química , Sinvastatina/farmacocinética , Distribuição TecidualRESUMO
Accumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high-affinity, selective kappa opioid antagonist that demonstrates >30-fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2-60 mg), multiple oral doses (2, 10, and 35 mg), and when co-administered with ethanol. Plasma concentrations of LY2456302 were measured by liquid chromatography-tandem mass spectrometry method. Safety analyses were conducted on all enrolled subjects. LY2456302 doses were well-tolerated with no clinically significant findings. No safety concerns were seen on co-administration with ethanol. No evidence for an interaction between LY2456302 and ethanol on cognitive-motor performance was detected. LY2456302 displayed rapid oral absorption and a terminal half-life of approximately 30-40 hours. Plasma exposure of LY2456302 increased proportionally with increasing doses and reached steady state after 6-8 days of once-daily dosing. Steady-state PK of LY2456302 were not affected by coadministration of a single dose of ethanol. No clinically important changes in maximum concentration (Cmax ) or AUC of ethanol (in the presence of LY2456302) were observed.
Assuntos
Benzamidas , Etanol , Antagonistas de Entorpecentes , Pirrolidinas , Receptores Opioides kappa/antagonistas & inibidores , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Adulto , Consumo de Bebidas Alcoólicas , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/sangue , Benzamidas/farmacocinética , Cognição/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Etanol/administração & dosagem , Etanol/sangue , Etanol/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Hidrocortisona/sangue , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/efeitos adversos , Antagonistas de Entorpecentes/sangue , Antagonistas de Entorpecentes/farmacocinética , Equilíbrio Postural/efeitos dos fármacos , Prolactina/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/sangue , Pirrolidinas/farmacocinética , Tempo de Reação/efeitos dos fármacosRESUMO
PURPOSE: No consistent method is available for finding stable warfarin maintenance doses and fast stabilization of international normalized ratio (INR) values among healthy subjects in experimental warfarin interaction studies. Using data from an earlier study that targeted a stable INR of 1.5-2.0 to test an interaction, we retrospectively evaluated potential dosing algorithms using all methods available to us to decrease the time needed for INR stabilization, which could be useful for future interaction studies in healthy subjects. METHODS: Published pharmacogenetic and clinical dosing algorithms used to initiate pharmacotherapy with warfarin were applied, predicted doses and actual doses were compared by regression analysis, and concentration-time profiles of S-warfarin were simulated using SimCYP® software. RESULTS: No demographic variables were significantly associated with time to reach a stable, low-intensity INR in this population of relatively young, healthy subjects. Predicted and actual doses were positively correlated for the pharmacogenetic algorithm, but not for the clinical algorithm. INR levels and S-warfarin concentrations were associated with CYP2C9 and VKORC1 genotypes. CONCLUSIONS: Induction to a pharmacodynamic steady state for warfarin for future multiple-dose warfarin drug-interaction studies in healthy volunteers may be predicted using a pharmacogenetic-based dosing algorithm. Simulations revealed that the desired subtherapeutic INR level may be achieved by reducing the predicted dose by approximately 15%. Further study is needed to assess the applicability of this approach to decrease attrition rates and the time needed to reach INR stabilization.
Assuntos
Anticoagulantes/administração & dosagem , Coeficiente Internacional Normatizado , Varfarina/administração & dosagem , Adulto , Algoritmos , Anticoagulantes/sangue , Anticoagulantes/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Simulação por Computador , Citocromo P-450 CYP2C9 , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/genética , Vitamina K Epóxido Redutases , Varfarina/sangue , Varfarina/farmacocinéticaRESUMO
BACKGROUND: Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. METHODS: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug-drug interactions (DDI) were assessed. RESULTS: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. CONCLUSION: No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile.
RESUMO
An increasing number of failures in clinical stages of drug development have been related to the effects of candidate drugs in a sub-group of patients rather than the 'average' person. Expectation of extreme effects or lack of therapeutic effects in some subgroups following administration of similar doses requires a full understanding of the issue of variability and the importance of identifying covariates that determine the exposure to the drug candidates in each individual. In any drug development program the earlier these covariates are known the better. An important component of the drive to decrease this failure rate in drug development involves attempts to use physiologically-based pharmacokinetics 'bottom-up' modeling and simulation to optimize molecular features with respect to the absorption, distribution, metabolism and elimination (ADME) processes. The key element of this approach is the separation of information on the system (i.e. human body) from that of the drug (e.g. physicochemical characteristics determining permeability through membranes, partitioning to tissues, binding to plasma proteins or affinities toward certain enzymes and transporter proteins) and the study design (e.g. dose, route and frequency of administration, concomitant drugs and food). In this review, the classical 'top-down' approach in covariate recognition is compared with the 'bottom-up' paradigm. The determinants and sources of inter-individual variability in different stages of drug absorption, distribution, metabolism and excretion are discussed in detail. Further, the commonly known tools for simulating ADME properties are introduced.
Assuntos
Fenômenos Químicos , Biologia Computacional , Desenho de Fármacos , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Fenômenos Farmacológicos , Relação Dose-Resposta a Droga , Humanos , Preparações Farmacêuticas/química , Fenômenos Farmacológicos/genética , Fenômenos Farmacológicos/fisiologia , Fatores de TempoRESUMO
PURPOSE: To establish the maximum-tolerated dose and evaluate tolerability, pharmacokinetics, pharmacodynamic effects, and antitumor activity of AEG35156, a second-generation antisense to X-linked inhibitor of apoptosis (XIAP) protein, in patients with advanced refractory malignant tumors. PATIENTS AND METHODS: This was a first-in-man, open-label, phase I dose-escalation study. AEG35156 was administered by continuous intravenous infusion over 7 days (7DI) or 3 days (3DI) of a 21-day treatment cycle. Dose escalation started at 48 mg/m(2)/d and continued until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Thirty-eight patients were entered in seven cohorts. Grade 3 to 4 adverse events were uncommon and were predominantly abnormal laboratory values: elevated ALT, thrombocytopenia, and lymphopenia. DLTs comprised elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia. The maximum-tolerated doses were defined as 125 mg/m(2)/d for the 7DI regimen and < or = 213 mg/m(2)/d for the 3DI schedule. AEG35156 area under the plasma concentration curve and peak plasma concentration increased proportionally with dose. Suppression of XIAP mRNA levels was maximal at 72 hours (mean suppression, 21%), and this coincided with a dramatic decrease in circulating tumor cells in a patient with non-Hodgkin's lymphoma. Two further patients had unconfirmed partial responses. Circulating biomarkers of cell death and apoptosis altered in association with drug infusion and toxicity. CONCLUSION: In this first-in-man study, AEG35156 was well tolerated, with predictable toxicities, pharmacokinetic properties, and clinical evidence of antitumor activity in patients with refractory lymphoma, melanoma, and breast cancer. Phase I/II trials of AEG35156 chemotherapy combinations are ongoing in patients with pancreatic, breast, non-small-cell lung cancer, acute myeloid leukemia, lymphoma, and solid tumors for which docetaxel is indicated.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/farmacocinética , Oligonucleotídeos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacocinética , Oligonucleotídeos Antissenso/efeitos adversos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
AIM: To assess the power of in vivo studies needed to discern the effect of genotype on pharmacokinetics (PK) and pharmacodynamics (PD) using CYP2C9 and (S)-warfarin as an example. METHODS: Information on the in vitro metabolism of (S)-warfarin and genetic variation in CYP2C9 was incorporated into a mechanistic population-based PK-PD model. The influence of study design on the ability to detect significant differences in PK (AUC(0-12 h)) and PD (AUEC(0-12 h) INR) between CYP2C9 genotypes was investigated. RESULTS: A study size of 90 (based on the natural abundance of genotypes and uniform dosage) was required to achieve 80% power to discriminate the PK of (S)-warfarin between wild type (*1/*1) and the combination of all other genotypes. About 250 subjects were needed to detect a difference in anticoagulant response. The power to detect differences between specific genotypes was much lower. Analysis of experimental comparisons of the PK or PD between wild-type and other individual genotypes indicated that only 21% of cases (20 of 95 comparisons within 11 PD and four PK-PD studies) reported statistically significant differences. This was similar to the percentage expected from our simulations (20%, chi(2) test, P = 0.80). Simulations of studies enriched with specific genotypes indicated that only three and five subjects were required to detect differences in PK and PD between wild type and the *3/*3 genotype, respectively. CONCLUSION: The utilization of prior information (including in vivo enzymology) in clinical trial simulations can guide the design of subsequent in vivo studies of the impact of genetic polymorphisms, and may help to avoid costly, inconclusive outcomes.
Assuntos
Anticoagulantes/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Coagulação Sanguínea/genética , Varfarina/farmacocinética , Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9 , Genótipo , Humanos , Modelos Biológicos , Polimorfismo Genético , Varfarina/administração & dosagemRESUMO
In vitro-in vivo extrapolation of clearance, embedded in a clinical trial simulation, was used to investigate differences in the pharmacokinetics and pharmacodynamics of dextromethorphan between CYP2D6 poor and extensive metabolizer phenotypes. Information on the genetic variation of CYP2D6, as well as the in vitro metabolism and pharmacodynamics of dextromethorphan and its active metabolite dextrorphan, was integrated to assess the power of studies to detect differences between phenotypes. Whereas 6 subjects of each phenotype were adequate to achieve 80% power in showing pharmacokinetic differences, the power required to detect a difference in antitussive response was less than 80% with 500 subjects in each study arm. Combining in vitro-in vivo extrapolation with a clinical trial simulation is useful in assessing different elements of study design and could be used a priori to avoid inconclusive pharmacogenetic studies.